Mechanisms of ATP Release from Glial Progenitors

神经胶质祖细胞释放 ATP 的机制

• 批准号: 7541747
• 负责人: Eliana Scemes
• 金额: $ 32.68万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541747
• 关键词: Applications Grants; Apyrase; Astrocytes; Bathing; Biochemical; Brain; Calcium; Calcium Oscillations; Cell Proliferation; Cells; Connexins; Connexon; Development; Diffusion; Enzymes; Event; Exocytosis; Gliosis; Goals; Image; In Vitro; Intracellular Second Messenger; Lytic; Measurement; Mediating; Neuroglia; Neuromodulator; Neurons; Neurotransmitters; Nucleotides; P2X-receptor; Paracrine Communication; Pathway interactions; Photons; Play; Property; Proteins; Purinoceptor; Role; Second Messenger Systems; Signal Transduction; Source; Staging; Stem cells; System; Time; Traumatic Brain Injury; autocrine; cell motility; extracellular; fluorescence imaging; glial cell development; luminescence; migration; nerve stem cell; prevent; progenitor; receptor; repaired

Nucleotide releasefrom glial cells plays important autocrine and paracrine signaling roles in the CMSand PNS. Recentstudies suggest that the non-lytic releaseof ATP from glial cells can either involve regulated exocytosis or efflux through nucleotide-permeable channels. Extracellular ATP acting onplasmalemmal ionotropic P2X and metabotropic P2Y receptors modulates neuronal activity, induces calcium transients in astrocytes and generatescritical intracellular second messengers implicated for instance in the development of gliosis following brain trauma and in the proliferation and migration of neural stem cells. Recently, we have obtained evidencethat neural progenitor cells display spontaneous calcium oscillations that are highly dependent on activation of P2Rs. Bath application of purinergic receptor antagonists or of the ATPdegrading enzyme apyrasepreventedthe occurrence of spontaneous calcium fluctuations. Moreover,blockade of P2Rs reduced the proliferation and the migration ratesof these progenitors. These results suggest that neural progenitors have the ability to release ATP,which then plays a crucial autocrine, paracrine signaling role during early CNS development.Although identification of pathways involvedon transmitter release from glial cells have been suggested for mature astrocytes, nothing is known about the developmental aspectsof the mechanism(s) by which ATP is released from precursors. Therefore, the goal of this grant application is to evaluate whether and at which stage of astrocyte development three of the putative pathways for transmitter release are functionally competent (excocytosis/secretion and diffusion through ionotropic P2XRs and connexin hemichannels) and to determine their contribution to calcium oscillations and cell migration. Immuocytochemical, biochemical and pharmacological approaches combined with luminescence and fluorecence imaging will be used to identify ATP release pathways. This identification is fundamental for the understanding of the signaling mechanisms ongoing during CNS development and repair.

核苷酸从神经胶质细胞中释放起来在CMSAND中起重要的自分泌和旁分泌信号传导作用 PNS。最近研究表明，非散散释放ATP从神经胶质细胞中可能涉及调节 通过核苷酸可渗透通道的胞吐作用或外排。细胞外ATP作用于质体的 离子型P2X和代谢性P2Y受体调节神经元活性，诱导钙瞬变 星形胶质细胞和产生涉及开发中涉及的临界细胞内第二使者 神经创伤后的神经胶质病以及神经干细胞的增殖和迁移。最近，我们有 获得的神经祖细胞所获得的表现出自发的钙振荡，这是高度的 取决于P2RS的激活。嘌呤能受体拮抗剂或atpdegrading的浴 酶apyraseprevented钙的自发钙波动的发生。而且，封锁 P2RS降低了这些祖细胞的增殖和迁移率。这些结果表明 神经祖细胞具有释放ATP的能力，然后播放至关重要的自分泌旁分泌信号传导 尽管鉴定了涉及的途径，但从 已经提出了成熟星形胶质细胞的神经胶质细胞，对发育方面一无所知 从前体释放ATP的机制。因此，此赠款申请的目标是 评估星形胶质细胞开发的阶段以及在哪个阶段 发射机释放在功能上是有能力的（吞噬作用/分泌和通过离子型P2XRS扩散 和连接素半通道），并确定它们对钙振荡和细胞迁移的贡献。 不合理细胞化学，生化和药理学方法结合发光和 荧光成像将用于识别ATP释放途径。这种标识对于 了解CNS开发和修复过程中正在进行的信号传导机制。